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Cellular Senescence Contributes to Impaired Heart Regeneration

This paper is a preprint, meaning it hasn't gone through peer review yet, so apply the appropriate multiple to its chances of containing significant errors. The authors outline evidence for the age-related accumulation of senescent cells to impair heart regeneration. I'd have to say that this is an expected outcome of cellular senescence, given what is presently known of senescent cells, and in particular the ways in which their potent mix of inflammatory signaling disrupts normal tissue function. Of course the scientific community still has to provide satisfactory proof for that to be the case for the heart specifically, and join the dots between the underlying mechanisms.

Since a number of senolytic therapies exist, treatments capable of selectively removing 25-50% of senescent cells from various tissues, it is the case that the best way to proceed in linking aspects of aging to cellular senescence is to destroy senescent cells and see what happens as a result. That is considerably faster and more efficient than purely investigative methods. The challenge here is that senolytic therapies clear senescent cells from most tissues, all tissues are affected in their own particular ways, and there are only so many researchers with the funding to carry out assessments. So while we'd all like to know how senolytics affect lymph nodes, or the stomach lining, or pick your favorite tissue type here, it will probably be a while before the research community works its way down the list to reach these line items.

Ageing is the greatest risk factor for many life-threatening disorders. Although long-term exposure to known cardiovascular risk factors strongly drives the development of cardiovascular pathologies, intrinsic cardiac aging is considered to highly influence the pathogenesis of heart disease. However, the fields of the biology of aging and cardiovascular disease have been studied separately, and only recently their intersection has begun to receive the appropriate attention.

Aging leads to increased cellular senescence in a number of tissues and work suggests senescent cell burden can be dramatically increased in various tissues and organs with chronological ageing or in models of progeria. Cellular senescence is associated with increased expression of the senescence biomarker, p16Ink4a (also known as Cdkn2a), impaired proliferation, and resistance to apoptosis. Senescent cells disrupt tissue structure and function because of the components they secrete, which act on adjacent as well as distant cells, causing fibrosis, inflammation, and a possible carcinogenic response. Indeed, senescent cells possess a senescence-associated secretory phenotype (SASP), consisting of pro-inflammatory cytokines, chemokines, and extracellular-matrix-degrading proteins, which have deleterious paracrine and systemic effects. Remarkably, even a relatively low abundance of senescent cells (10-15% in aged primates) is sufficient to cause tissue dysfunction.

Here we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease aged 32-86 years. In aged subjects (older than 74 years) over half of CPCs are senescent, unable to replicate, differentiate, regenerate, or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs senescent. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (using the INK-ATTAC model or wild-type mice treated with dasatinib and quercetin senolytics) in vivo activates resident CPCs and increased the number of small, proliferating cardiomyocytes. Thus therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.

Link: https://doi.org/10.1101/397216

Comments

Nothing surprising here but still yet another be research confirming the benefits of senolitics

Posted by: Cuberat at December 5th, 2018 8:03 AM

@ira

Senolytics by definition have to be toxic . Ideally only to the senecent cells. For now, they have wide off-site effects.

For example, qercetin is one of the weak senolytics . It works by inhibiting autophagy. That alone is undesirable since can push many cells to cenescence. However, when combined with Dasatinib the reduced autophagy helps killing more SC.

There goal is to limit the off-site toxicity. Senolitics will require safety protocols and efficacy studies.

Posted by: Cuberat at December 5th, 2018 11:15 AM

Looking forward to Senolitics therapy. Looking forward to next years results on the clinical studies. Looking forward to the first rejuv therapy. Hoping for additional therapies to be available quicker.

Posted by: Robert at December 5th, 2018 11:55 AM

Schlegel and Liu demonstrated that the combination of feeder cells and a Rho kinase inhibitor (Y-27632) induces normal cells from many tissues to proliferate indefinitely in vitro. This process occurs without the need for transduction of exogenous viral or cellular genes. These cells have been termed "Conditionally Reprogrammed Cells (CRC)". The induction of CRCs is rapid and results from reprogramming of the entire cell population. CRCs do not express high levels of proteins characteristic of iPSCs or embryonic stem cells (ESCs) (e.g., Sox2, Oct4, Nanog, or Klf4). This induction of CRCs is reversible and removal of Y-27632 and feeders allows the cells to differentiate normally. CRCs retain a normal karyotype and remain nontumorigenic. The activity of the conditioned medium correlates directly with radiation-induced feeder cell apoptosis. Thus, conditional reprogramming of epithelial cells is mediated by a combination of Y-27632 and a soluble factor(s) released by apoptotic feeder cells.(https://en.wikipedia.org/wiki/Induced_stem_cells#Conditionally_reprogrammed_cells)
Why I am writing about this. I believe that it is possible to activate the proliferation of progenitor cells in vivo under the influence of aged cells apoptosis products formed under the action of the senolytics if at the same time to treate the tissues with Y-27632. This drug is not toxic and does not cause noticeable side effects. It is worth checking drug combination of senolytics + Y-27632 on the mice.

Posted by: Dmitry Dzhagarov at December 6th, 2018 12:35 AM

Good find Dmitry. Can you elaborate on how apoptosis products could substitute for the feeder cells used in vitro?

Posted by: Mark at December 6th, 2018 7:07 AM

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